Ligand-Controlled Asymmetric Arylation of Aliphatic Amino Anion Equivalents
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Zhu, Ye, and Stephen L. Buchwald. “Ligand-Controlled
Asymmetric Arylation of Aliphatic -Amino Anion Equivalents.”
Journal of the American Chemical Society 136, no. 12 (March
26, 2014): 4500–4503. © 2014 American Chemical Society
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http://dx.doi.org/10.1021/ja501560x
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American Chemical Society (ACS)
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Communication
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Ligand-Controlled Asymmetric Arylation of Aliphatic α‑Amino Anion
Equivalents
Ye Zhu and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
*
Table 1. Pd-Catalyzed Arylation of Imine 2aa
ABSTRACT: A palladium-catalyzed asymmetric arylation
of 9-aminofluorene-derived imines using a chiral dialkylbiaryl phosphine as the supporting ligand has been
developed. This transformation allows for enantioselective
access to a diverse range of α-branched benzylamines.
C
hiral amines serve as key intermediates in natural product
synthesis1 and are prevalent building blocks in the
preparation of pharmaceuticals. Moreover, enantioenriched
amines are widely employed as chiral auxiliaries,2 ligands,3
catalysts,4 and components of supramolecular materials.5 As a
result, considerable effort has been directed toward their
enantioselective synthesis.6−9 While the addition of carbanions
to electrophilic CN double bonds has been widely
applied,10,11 the use of nucleophilic α-amino anions for the
synthesis of chiral amines (except α-amino acids) has been less
studied.12 Several methods that take advantage of these valuable
anions (or their equivalents) use Pd catalysis to achieve
asymmetric arylation, where the chirality is introduced by a
preformed reagent.13 Alternatively, the enantioselective synthesis of diarylmethanamines was realized using Cr(CO)3
complexes of N-benzyl dialkylamines, and the asymmetry is
controlled by the ligand.14 However, there are no examples of
similar processes that utilize the catalytic functionalization of αamino anion equivalents of acyclic aliphatic amines to arrive at
enantioenriched α-alkyl benzylamines.15 Herein we report the
realization of such a method that employs a ligand-controlled
Pd-catalyzed asymmetric arylation process.
We began by exploring 2-azaallyl anions16 as aliphatic αamino anion equivalents. As outlined in Scheme 1, deprotonation at the α′-position of aldimine (c), derived from aliphatic
aldehyde (a) (R = alkyl group) and diarylmethanamine (b),
generates the corresponding 2-azaallyl anion (d).17,18 A
a
Reaction conditions: PhBr (0.25 mmol), 2a (0.325 mmol), NaOtBu
(0.275 mmol). Flu = 9-fluorenyl. TMS = trimethylsilyl. bIsolated yields
of 4a. cThe ee (enantiomeric excess) of 4a was determined by chiral
HPLC.
subsequent Pd-catalyzed asymmetric arylation of (d) affords
α-alkyl benzylamine (f) upon deprotection of ketimine (e).
The overall transformation effectively converts a carbonyl
compound to an α-branched amine via electrophilic substitution at the carbonyl carbon.19 We postulated that the
reactivity of (d) could be modulated by incorporating
appropriate Ar′ substituents, while the development of a chiral
catalyst would allow for effective enantiocontrol of the
transformation.
At the outset, we chose 9-aminofluorene-derived imine 2a as
the nucleophilic coupling partner for the Pd-catalyzed arylation
reaction (Table 1).20 A survey of chiral phosphorus ligands and
reaction conditions revealed that 2a underwent the proposed
transformation using NaOtBu as the base and (R)-iPrTrixiePhos (L1) as the supporting ligand, affording 9-fluorenylamine 4a in 82% yield with 86% ee upon reduction of 3a (entry
Scheme 1. Proposed Pd-Catalyzed Arylation Reaction
Received: February 13, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Scheme 2. Pd-Catalyzed Arylation of Imine 2ba
Encouraged by our initial results, we evaluated the effect of
altering the structure of the supporting ligand by changing the
substituents on the phosphorus center.23 While diminished
enantioselectivity was obtained when (R)-cyclopentylTrixiePhos (L2) or (R)-CyTrixiePhos (L3) was employed (Table 1,
entries 2 and 3), the use of (R)-cycloheptylTrixiePhos (L4) as a
supporting ligand yielded the product with slightly increased ee
(entry 4).24 Additionally, an improvement in ee was observed
when the reaction was performed in cyclohexane instead of
toluene (entry 5). Further optimization of the phosphorus
ligand focused on introducing substituents on the binaphthyl
backbone of L4.25 Examination of 4′-substituted cycloheptylTrixiePhos derivatives L5−L726 showed that the electronic and
steric properties of the 4′-substituent indeed influenced the
outcome of the reaction. For example, a ligand with a πdonating NMe2 substituent (L5; entry 6) gave the product with
a lower level of enantioselectivity than L4, while the yield
diminished when an electron-withdrawing cyano group was
introduced (L6; entry 7). However, when a bulky TMS
substituent was installed (L7; entry 8), the enantioselectivity
was increased while retaining the reactivity.
a
Reaction conditions: see Table 1. The rr (regioisomeric ratio, 3b to
5) was determined by 1H NMR spectroscopy for the corresponding
amines upon NaBH4 reduction.
1).21 In contrast, the related diphenylmethanamine-derived
imine did not participate in the reaction under the same
conditions. This difference in reactivity apparently arises from
the rigid fluorenyl substituent, which becomes aromatic upon
deprotonation and enforces coplanarity to stabilize (d) through
π-conjugation.22
Scheme 3. Pd-Catalyzed Enantioselective Arylation Reactionsa,b
a
Reaction conditions: Ar−X (1 mmol, X = Br unless otherwise noted), 2 (1.15 mmol), NaOtBu (1.1 mmol). Isolated yields (averages of two runs)
are shown. Boc = tert-butoxycarbonyl. Ts = p-toluenesulfonyl. bThe absolute configuration of 6c was assigned as S. See the Supporting Information
for details. c[(η-C3H5)PdCl]2 (5 mol %), L7 (12.5 mol %), 2 (1.25 mmol), NaOtBu (1.2 mmol). dThe ee was determined for the corresponding NBoc amine. e2 (1.05 mmol).
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described in the paper from which SLB and former/current
coworkers receive royalty payments.
The regiochemical outcome of the transformation was also
influenced by the phosphorus ligand. In the course of the
reaction, the 2-azaallyl anion can potentially undergo arylation
at either the α- or α′-carbon (Scheme 2).17 Unlike the reaction
of imine 2a, which yielded 3a as the only cross-coupled
product, the isobutyraldehyde-derived imine 2b afforded a
mixture of regioisomers 3b and 5. Presumably, 3b was favored
because the α-carbon is the less hindered position. When L7
was employed as the supporting ligand, 3b was produced with
improved enantioselectivity and regioselectivity compared with
when L4 was employed. Therefore, L7 was used for the
remainder of our study.
With the optimized reaction conditions, the Pd-catalyzed
arylation was successfully applied to a range of substrates
(Scheme 3). Reduction of the 9-fluorenimine products (3)
afforded 9-fluorenylamines (4). Subsequently, 4 could be
readily deprotected under hydrogenolysis conditions, yielding
the corresponding N-Boc amines (6a and 6b) in the presence
of Boc2O. Alternatively, acid-mediated hydrolysis of 3 provided
direct access to amines (7), which could be converted to N-Boc
amines (6c−6f). Various aryl halides possessing electron-rich
(e.g., 4b and 6b) and electron-deficient (e.g., 4d and 4e)
substituents, including carbonyl groups (7c and 7d), participated in the transformation, furnishing the amine products with
high enantioselectivity. In addition to aryl bromides, the
reactions proceeded equally well using an aryl iodide (4e) and
an aryl triflate (6a) as substrates.27 Notably, heteroaromatic
halides, including bromo-substituted thiophene (6e), quinoline
(6f), pyridine (7a), and indole (7b), proved to be suitable
coupling partners for this transformation, although a lower level
of enantioselectivity was observed with an ortho-substituted
aryl bromide (4h). Various imines derived from aliphatic
aldehydes underwent the desired arylation reactions. However,
the reaction of a sterically demanding 2-ethylbutyraldehydederived imine yielded a significant amount of regioisomer 8
along with 4i. It should be noted that the imine of
trimethylacetaldehyde was unreactive, presumably because of
the steric hindrance introduced by the adjacent tert-butyl group.
In conclusion, we have developed a Pd-catalyzed arylation of
9-aminofluorene-derived imines that uses a chiral dialkylbiaryl
phosphine L7 as the supporting ligand. This transformation
accommodates a broad scope of aryl halides and is effective for
imines derived from various aliphatic aldehydes. A diverse range
of α-branched benzylamines was prepared with high
enantioselectivity. The application of this method to imines
derived from aromatic aldehydes and ketones and the
development of vinylation and alkylation28 of 2-azaallyl anions
are under investigation.
■
■
ACKNOWLEDGMENTS
The research reported in this publication was supported by the
National Institutes of Health under Award GM58160. This
activity was supported in part by an educational donation
provided by Amgen. We also thank Dr. A. C. Sather (MIT) and
Mr. J. R. Colombe (MIT) for help with preparation of the
manuscript.
■
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ASSOCIATED CONTENT
S Supporting Information
*
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
REFERENCES
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
Notes
The authors declare the following competing financial
interest(s): MIT has or has filed patents on ligands that are
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